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The splicing factor DHX38/PRP16 is required for ovarian clear cell carcinoma tumorigenesis, as revealed by a CRISPR-Cas9 screen

ABSTRACT: Certain cancers, such as ovarian clear cell carcinoma (OCCC), display high levels of genetic variation between patients, confounding the development of effective therapies. In order to identify novel genes critical to OCCC growth, we employed the pooled genome-scale CRISPR Knock-Out (GeCKO) v2 CRISPR-Cas9 knockout screening system using the OCCC cell line JHOC5, as well as the T-antigen immortalized normal ovarian surface epithelium cell line OSE3 as a negative control. We identified the gene encoding DHX38/PRP16, an ATP-dependent RNA helicase involved in splicing, as critical for the growth and tumorigenesis of OCCC; DHX38 knockdown in OCCC cells, but not normal cells, induces apoptosis and impairs OCCC tumorigenesis in a mouse model. Our results suggest that DHX38/PRP16 may play a role in OCCC tumorigenesis, and can be regarded as a promising therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188485 | GEO | 2022/01/19

REPOSITORIES: GEO

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The phosphate exporter XPR1/SLC53A1 is required for the tumorigenicity of ovarian cancer.

Project description:Ovarian cancer is the fifth cause of cancer-related death in women. Ovarian clear cell carcinoma (OCCC) is a chemotherapy-resistant epithelial ovarian cancer with poor prognosis. As a basis for the development of therapeutic agents that may improve the prognosis of OCCC, we performed a screen for proteins critical for the tumorigenicity of OCCC using the CRISPR/Cas9 system. Here we show that knockdown of the phosphate exporter XPR1/SLC53A1 induces the growth arrest and apoptosis of OCCC cells in vitro. Moreover, we demonstrate that knockdown of XPR1/SLC53A1 inhibits the proliferation of OCCC cells xenografted into immunocompromised mice. These results suggest that XPR1/SLC53A1 plays a critical role in the tumorigenesis of OCCC cells. We speculate that XPR1/SLC53A1 might be a promising molecular target for the therapeutic treatment of OCCC.

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A genome-wide CRISPR/Cas9 screen identifies therapeutic targets required for the tumorigenesis of ovarian clear cell carcinoma (OCCC).

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Gene expression profiling of epithelial ovarian cancer by bulk RNA-seq

Project description:Ovarian cancer has one of the worst prognoses among gynecologic malignancies. About 60% of ovarian cancer cases are diagnosed at Stages III and IV, and their five-year survival rate is less than 30%. Ovarian cancer is classified into four major histological subtypes; serous, clear cell, endometrioid and mucinous. Ovarian clear cell carcinoma (OCCC) is less sensitive to conventional platinum-based chemotherapy and has worse prognosis than other subtypes. In this study, we attempted to identify novel molecular targets critical for the proliferation and tumorigenicity of OCCC using the CRISPR/Cas9 system, and identified some genes as important candidates. Some of these candedates were upregulated in ovarian cancer tissue, especially OCCC. Our results suggest that not only may be these candedates a promising diagnostic maker for OCCC, drugs against these candedates would be useful for the therapeutic treatment of OCCC.

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Expression Data from HNF1b-knockdown RMG2-ovarian cancer cells

2012-05-01 | GSE37290 | GEO

Expression Data from HNF1b-knockdown RMG2-ovarian cancer cells

Project description:Ovarian clear cell carcinoma (OCCC) is a morphologically and biologically distinct subtype of ovarian carcinomas. We previously reported a gene expression profile characteristic of OCCC (OCCC signature), which contains hepatocyte nuclear facter-1b ( HNF-1b). To elucidate the biological role of HNF-1b in OCCC, we performed the suppression of the HNF-1b expression in human ovarian cancer cell line RMG2 using short hairpin RNA. We are now evaluating the functional effect using these cells. Affimetrix Human Genome U133A plus 2.0 chips was conducted for HNF1b knockdown and non-silencing cells (five replicates each for RMG2-HNF1b-sh1 and RMG2-HNF1b-sh2, ten replicates for the RMG2-control). All specimens were arrayed in parallel and used for RMA normalization.

2012-04-30 | E-GEOD-37290 | biostudies-arrayexpress

PPP2R1A mutations cause ATR inhibitor synthetic lethality in ARID1A deficient ovarian clear cell carcinoma

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2011-05-16 | E-GEOD-29175 | biostudies-arrayexpress

Profiling of circRNA Expression in Human Ovarian Clear Cell Carcinoma (OCCC)

Project description:To identify highly expressed circular RNAs (circRNAs) in OCCC and elucidate their function, we performed a circRNA microarray analysis using two OCCC clinical samples and their corresponding normal ovarian tissues from the opposite side, screening 13,617 circRNAs.

2024-05-17 | GSE266248 | GEO

Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C (Affymetrix)

Project description:Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of ‘105C’, a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology. Copy number variation was determined for multiple Ovarian Clear Cell Carcinomas

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